The proposed research will examine two primary objectives in the overall research program. In addition to research using behaviorally characterized young (6 months) and aged (24-35 months) rats obtained from the Animal Research Core, several studies will involve the use of young rats with experimental manipulations intended to model certain features of aged rats with cognitive impairment. In a series of experiments (Aim #1) we will examine neurogenesis in the dentate gyrus of the hippocampal formation. Proliferation, survival and differentiation of newly generated cells in the dentate gyrus will be studied, comparing young (6 months) and aged (25 months) behaviorally characterized rats. Rats at 12 months of age will also be included in these studies based on evidence for a significant decrease in neurogenesis by 12 months of age in other rat strains. Proposed research in Aim #2 will address mechanisms that may control neurogenesis in aging, as well as neuroprotective mechanisms relevant to the condition of other hippocampal/cortical neurons. GR-mediated transcription, and in particular its interaction with NFkappaB, regulates genes that may reduce neurogenesis as well as the integrity of cell function and survival. Of particular interest for the research on neurogenesis under Aim 1 is the status of gene expression for the proto-oncogene bcl-2 family (Bcl-2, Bax, Bcl-XL). We will examine the mRNAs, as well as target mRNAs for MnSOD and heme oxygenase-1 in hippocampus and interconnected cortical networks using in situ hybridization histochemistry. Finally, we have designed a series of experiments to examine neural plasticity of CA1 synapses in the in vitro hippocampus taken from behaviorally characterized young and aged rats. This work will use methods designed to resolve mechanistically distinct forms of LTP and LTD. We focus in particular on an NMDA-independent form of LTD, which is induced via activation of PLCbeta1. In other research in this program project we have established that signaling through this pathway via both mGLUr (Type 1) and mAChr is blunted, with a greater decrease strongly correlated with cognitive decline in aged rats. The research on neural plasticity in this project is linked to complementary in vivo studies in Project 1 (Eichenbaum). Our proposed research on neurogenesis and the condition of pathways that control neuronal survival and apoptosis is also strongly linked to work on other projects (Projects 3-5). Our approach has significant potential for increasing our understanding of the aging process and for assessing the therapeutic potential for specific neurobiological interventions.